Cyclocarbonate esters of 16alpha, 17alpha-dihydroxypregnenes



United states patent @i 3,d5d,5l9 Patented Aug. 21, 1962 ice 3,050,519CYCLQQARBEBNATE 6F ret in- DEHYDRGXYPREGNENEfi Josef Fried, Princeton,Ni, assigner to @iin Mathieson Chemical Corporation, New York, N31, acorporation of Virginia N Drawing. Filed May 13, W69, Ser. No, 28,333Claims. (Ci. lat -239.55)

This invention relates to, and has for its object, the provision of amethod for preparing physiologically active steroids and to thephysiologically active steriods produced thereby.

The steroids of this invention include the 160:,17oc-CyC1O- carbonateesters of l6cx,l7a-dihydroxy steroids of the pregnene seriesunsubstituted in the (Ming, which series includes, inter alia, compoundshaving either a pregnene, a pregnadiene, or a pregnatriene nucleus. Moreparticularly, this invention includes 16a,17ot-cyclocarbonate esters ofpregnenes represented by the following general formula:

CHZZ

wherein the 1,2 and/or 6,7 positions are saturated or double bonded; Qis hydrogen or methyl; R is hydrogen, lower alkyl" (especially methyl)or halo in either the alpha or beta position; and Z is hydrogen, halogen(especially chloro and fluoro), hydroxy or the acyloxy radical of ahydrocarbon carboXylic acid of less than ten carbon atoms, such as analkanoic acid especially the lower alkanoic acids (e.g., acetic acid,propionic acid, and hexanoic acid), a monocyclic aromatic carboxylicacid (e.g., benzoic acid, and o, m and p-toluic acids), a monocycliclower aralkanoic acid (e.g., phenylacetic acid and [i-phenylpropionicacid), a lower alkenoic acid, a lower cycloalkanoic acid, or a lowercycloalkenoic acid.

Among the compounds of this invention there may be mentioned thel6ot,l7u-cyclocarbonate esters of C-ring unsubstituted16oc,17(1-dihydroxyprogesterones, which class of esters includes thefollowing:

I. The 160:,17oa-CYC1OC3IbOI13t6 esters of 6-halogenated16m,17a-dihydroxyprogesterones, especially the 16a,l7 xcyclocarbonateesters of 6-fluoro and 6-ChlO1O-16oc,17ocdihydroxyprogesterones, such asthe l6ot,l7a-cyclocarbonate esters of6ot-fluoro-16a,17a-dihydroxyprogesterone, the 16u,17a-cyclocarbonateester of 6,8,21-dich1oro-l6a,17otdihydroxyprogesterone, thel6a,l7a-cyclocarbonate ester of 6(3-fluoro-l6a,l7a-dihydroxy 1dehydroprogesterone, and the 16a,17a-cyclocarbonate ester of60rL-fillOfO160, 1701,21-trihydroxyprogesteroue and 21-esters thereof(e.g. the 2l-acetate);

II. The 16a,17a-cyclocarbonate esters of 6-l0weralkylated-l6a,l7u-dihydroxyprogesterones, especially the 160:,l7oc-cyclocarbonate esters of 6-methyl(orethyl)-l6u,l7adihydroxyprogesterones, such as the 16a,17a-cyclocarbonateester of 6ot-methyl-16a,17ct-dihydroxyprogesterone, thel6a,17cx-CYC1OC2IbOI1Elt6 ester of6/i-methyl-16u,17a-dihydroxyprogesterone, the 16a,17u-cyclocarbouateester of 6B-ethyl-16a,17u-dihydroxyprogesterone, the16a,l7a-cyclocarbonate ester of 6tx-ethyl-l6a,l7mdihydroxyprogesterone,the l6a,l7a-eyclocarbonate ester of 6a-methyl-21-fiuoro-l6a,17a-dihydroxyprogesterone, the 16a,17a-cyclocarbonate esterof 6a-methyl-16a,17a-dihydroXy-1-dehydroprogesterone, and the16a,17a-cyclocarbonate ester of6a-methy1-16a,17u,21-trihydroxyprogesterone and 21- esters thereof(e.g., the 2l-acetate);

*III. The 16u,17u-cyclocarbonate esters of 6-dehydro-;,l7a-dihydroxyprogesterones, such as the 16cz,170ccyclocarbonate esterof 6'dehydro-16a,l7ot-dihydroxyprogesterone, the 16a,17a-cyclocarbonateester of A pregnatriene-l6a,17u-diol-3,20-dione, the 1606,170L-CYC10-carbonate ester of 6-dehydro-l6u,17a,21-trihydroxyprogesterone and21-esters thereof (e.g., the Zl-acetate) and the1604,17wCYC10CflIb01'18t6 ester of6-dehydro-l6fimethyl-16a,l7a-dihydroxyprogesterone; and

IV. The 16a,17o-cyclocarbonate esters of fi-unsubstitutedl6a,17a-dihydroxyprogesterones, such as the 16a, l7ct-cyclocarbonateester of 16a,17a-dihydroxyprogesterone, the 16a,17a-cyc1ocarbonate esterof 21-fluorol6a,17wdihydroxyprogesterone, the 16a,17u-cyclocarbonateester of 16a,17a-dihydroxy-l-dehydroprogesterone, the16a,17a-cyclocarbonate ester of l6tx,l7ot,2l-trihydroxyprogesterone and21-esters thereof (e.g. the 2l-acetate), and the l6a,l7a-cyclocarbonateester of 16,8-methyl- 1 60, 1 7tx-dihydroxyprogesterone.

The compounds of this invention can be prepared by a process of thisinvention which comprises reacting a steroid of the general formula:

wherein the 1,2 and/or the 6,7 positions are saturated or double bonded;R and Q are as hereinbefore defined and Z is hydrogen, halogen (cg.chloro or fluoro) or an acyloxy radical of a hydrocarbon carboxylic acidof the group hereinbefore defined, with phosgene in the presence of anhydrogen chloride acceptor, such as an organic nitrogen base (e.g.,pyridine, collidine, triethanolamine and quinoline), and recovering the16,17-cyclic ester thus formed. The reaction is preferably carried outat temperatures below 0 C. by treating a solution or suspension of thesteroid in the basic medium with phosgene and then recovering theproduct by conventional procedures.

The steroidal starting materials for preparation of the compounds ofthis invention are, generally, C-ring unsubstituted derivatives of16,l7-dihydroxyprogesterones. Among the suitable steroidal startingmaterials there may be mentioned inter alia:

I. 6-hal0genated-16a,17a dihydroxyprogesterones, especially 6-fluoro and6-chloro-dihydroxyprogesterones, such as6u-fiuoro-l6a,17a-dihydroxyprogesterone, and 21- esters of 6a fluoro16a,17a,21 trihydroxyprogesterone (egg the ZI-acetate);

II. 6-lower alkylated-l60,l7a-dihydroxyprogesterones, especiallyo-methyl (or ethyl)-l6a,l7a-dihydroxyprogesterones, such as 6e:metl1yl-l6a,l7wdihydroxyprogesterone, 6a ethyl16a,l7a-dihydroxyprogesterone, 6ame'thyl l6a,l7adihydroxy-l-dehydroprogesterone, and Zl-esters of6ot-methyl-16a,1706,2l-trihydroxyprogesterone (e.g., the Ill-acetate);and

HI. 6 unsubstituted 16a,l7a-dihydroxyprogesterones,

J) such as 16a,l7ot dihydroxyprogesterone, 1604,17oc-dihY-droxy-l-dehydroprogesterone, 21 esters of 16,06170t,21-trihydroxyprogesterone (e.g., the 2l-acetate) and 16,5-methyl-16a,l7a-dihydroxyprogesterone.

Where a particular l-dehydro steroid is desired and only thecorresponding 1,2-saturated derivative is available, the latter can beconverted to the former by 1,2-dehydrogenation with Bacteriumcyclooxydans in accordance with the method set out in Example 1 of US.Patout No. 2,822,318.

The 6-halo-l6a,l7a-dihydroxyprogesterones used herein are described incopending application Serial No. 7,521, filed February 9, 1960. The6-I1'l5il1Yl-160c,170tdihydroxyprogesterone starting materials usedherein are described in application Serial No. 830,467, filed July 30,1959.

The 2l-acyloxy-l6,17-esters of this invention can be prepared by thealternative process which comprises treating the16a,17o,2l-trihydroxyprogesterone starting material with acetone andperchloric acid followed by treatment with an acid anhydridecorresponding to the acyloxy radical desired to yield the1606,170L-3C6t01'llCl6-2lacylate which is treated with formic acid tohydrolyze the 16,17-ketal group. The l6ot,l7u,2l-trihydroxy-2lacylatederivative is converted to its l6,17--cyclic ester by the hereinbeforedescribed treatment with phosgene.

The 2l-halogenated esters of this invention can alternatively beprepared by treating the corresponding 16,041711,2l-trihydroxyprogesterone with acetone and perchloric acid to yield thecorresponding 16,17-acetonide and treating the latter with an organicsulfonyl halide such as mesyl chloride or tosyl chloride to form the2l-sulfonyloxy-16,17-acetonide derivative which is then treated with analkali metal halide such as lithium chloride, lithium bromide, sodiumiodide or potassium bifluoride to yield the corresponding 2l-chloride,bromide, iodide, or fluoride, respectively. The 2l-halo-16,17-acetonidesare d acetonated by hydrolysis with an acid (e.g. formic acid) and thentreated with phosgene, as hereinbefore described, to yield the desired16,17-carbonate esters of this invention.

The 6-dehydro-l6,l7-esters of this invention may be prepared by reactingthe corresponding 6,7-saturated starting material with a6,7-dehydrogenating agent (e.g., chloranil in a mixture of ethyl acetateand acetic acid) and separating the 6-dehydroderivative thus formed.

The l6fi-methyl-l6,17-esters of this invention are prepared byketalizing a 16-methyl-A -pregnadiene-S-ol- 20-one with a lower alkyleneglycol in the presence of an acid catalyst (e.g. toluenesulfonic acid),treating the resulting 20-ethylene ketal derivative with an oxidizingagent such as aluminum tertiary butoxide in cyclohexanone to form thecorresponding A -3-one which is then converted to 16 3 methyll6a,l7ot-dihydroxyprogesterone 20-ethylene ketal by treatment wi hosmium tetroxide followed by a reducing agent such as hydrogen sulfide.The dihydroxy compound is converted to its cyclic carbonate ester by atwo step process involving either hydrolysis of the ZO-ketal group withan acid (e.g., sulfuric acid) and then esterification at the16,17-positions or first esterification at the 16,17-positions and thenhydrolysis of the ketal radical with an acid (e.g., perchloric acid).

The 6B-methyl and 6,8-halo cyclic esters of this invention are preparedby treating a 6fi3-methylpregnane-5a,16a, 17a-triol-3,20-dione (preparedas disclosed in my copending application Serial No. 830,467, filed July30, 1959) or the corresponding 6fl-halo-triol (described in the sameapplication) with phosgene in an organic base as hereinbefore disclosedto simultaneously esterify the 16,17-position and dehydrate the4,5a-position thereby yielding 6,8- methyl 1604,17 dihydroxyprogesteronel6ix,l7u-cyclie ester or the 6t3-halo-l6oc,17u-dihydroxyprogesterone16a, l7e-cyclic ester, respectively.

If a 2l-acyloxy steroid is employed as the starting material and thecorresponding 21-hydroxy steroid is desired as the final product, theZl-acyloxy-l6ot,17ot-dihydroxyprogesterone l6ot,17u-CYCllC ester productis hydrolyzed as by treatment with an alkali metal carbonate (e.g.potassium carbonate) to yield the desired free 2l-hydroxy final product.Alternatively, the 21-acyloxy products of this invention may beconverted to the corresponding 11 3- hydroxy-Zl-acylox derivatives byknown methods [such as by subjecting the 21-acyloxy-ll-desoxy-startingmaterial to microbiological oxidation by the enzymes of Cunninghamellablakesleeaiza as disclosed in Steroids, Fieser, p. 673 (1959)].

The compounds of this invention as represented by Formula I arephysiologically active substances which possess progestational andanti-uterotrophic activity and hence can be used in lieu of knownprogestational agents, such as progesterone, in the treatment ofdiseases and conditions such as habitual or threatened abortion,amenorrhea, metropathic hemorrhagica, dysmenoirhea, inadequate corpusluteum function and premenstrual tension, being formulated for suchadministration in the usual perorally or parenterally acceptableformulations.

The following examples illustrate, without limiting this invention (alltemperatures being in degrees centigrade):

EXAMPLE 1 1 6a,] 7a-Dilzydroxyprogesterone 16ot,17a-Carb0nate To asolution of 1.5 g. of 16a,l7a-dihydroxyprogesterone in 30 ml. ofanhydrous pyridine is added at with stirring 18.8 ml. of a solution ofphosgene in toluene. The reaction is allowed to proceed for 20 minutesat 0 when ice and water is added and the mixture taken up in chloroform.The chloroform extract is washed with water, 1 N sulfuric acid, water,dilute sodium bicarbonate and again with water, dried over sodiumsulfate and the solvent removed in vacuo. The resulting residue afterrecrystallization from acetone-hexane furnishes pure 16a,17e-dihydroxyprogesterone 16a,l7 x-carbonate having the followingproperties: M.P. about 240; +l32 (0., 1.67 in chlf.);

g, 238 111a 6:14,?00 mi 5.50, 5.82, 5.95 and 6.18

Analysis.-Calcd for C H O (372.44): C, 70.94; H, 7.58. Found: C, 71.06;H, 7.41.

EXAMPLE 2 16a,I7ot-Dihydroxy-J-Dehydropr0gester0ne 1611,] 7ot-Carb0nateTo a solution of 1.5 g. of 16a,17e-dihydroxy-1-dehydroprogesterone(prepared by dehydrogenating 1605,170t-dihydroxyprogesterone withBacterium cyclooxydans in accordance with Example 1 of US. Patent No.2,822,318) in 30 ml. of anhydrous pyridine is added at 0 with stirring18.8 ml. of a 10% solution of phosgene in toluene. The reaction isallowed to proceed for 20 minutes at 0 when ice and Water is added andthe mixture is taken up in chloroform. The chloroform extract is washedwith water, 1 N sulfuric acid, water, dilute sodium bicarbonate andagain with Water, dried over sodium sulfate and the solvent removed invacuo leaving the product 16a,l7adihydroxy-l-dehydroprogesteronel6u,l7a-carbonate.

EXAMPLE 3 160a,] 7ot,2 1 -T rihydroay progesterone 1 6 (1,1 7 a-Carbonate-Z] -A cetate Following the procedure of Example 1,16a,17a,21-trihydroxyprogesterone ZI-acetate (prepared by treating 100mg. of 16ot-hydroxycortexolone with acetone and 0.01 ml. of 70%perchloric acid to yield the 16,17-acetonide derivative ofl6u-hydroxycortexolone which is first transformed to its 2l-acetate bytreatment with pyridine and acetic anhydride and then to the desired16u-hydroxycortexolone 21-acetate by hydrolysis of the 16,17-ketal groupwith aqueous formic acid) is treated with a phosgene to yield theproduct 16u,17u,21-trihydroxypro gesterone 16a,17a-carbonate 21-acetate.

EXAMPLE 4 16/3-Methyl-16a,]7a-Dihydroxyprogesterone 16u,17a-Carbonate A.PREPARATION OF A -1G-METHYLPREGNADIENE-3fl OL-20LONE-2O-ETHYLENE KETAL Amixture of 3 .g. of A -l6-methylpregnadiene-3B- ol-20one, 9 ml. ofethylene glycol and 112 m1. of benzene is heated at reflux with stirringwith the aid of a Dean- Stark separator. When 20 ml. of benzene hasdistilled, 186 mg. of toluene sulfonic acid rnonohydrate is added to themixture and the reaction is allowed to proceed with stirring for 16hours at reflux temperature. After cool ing, the mixture is neutralizedby the addition of sodium bicarbonate solution followed by the additionof water. The layers are separated, the benzene extract washed withwater, dried over sodium sulfate and evaporated to dryness in vacuo. Thecrystalline residue after recrystallization from acetone furnishes thepure ketal of the following properties: MP. about 168169; [a] 82 (c.,1.25 in chlf.).

Analysis.Calcd for (3 1-1 (372.53): C, 77.34; H, 9.74. Found: C, 77.22;H, 9.40.

B. PREPARATION OF AIJB-IGJMIETHYLPREGNADIENE- 3,20-DIONE-20-ETHYLENEKETAL A solution of 2.5 g. of A -l6-rnethylpregnadiene-3B- ol-20-one20-ethylene ketal in a mixture of 90 ml. of xylene and 30 ml. of freshlydistilled cyclohexanone is distilled until ml. of distillate have beencollected. To this solution is added 2.5 g. of aluminum tertiarybutoxide and the resulting solution is refluxed for 50 minutes. Water isadded and after separation of the layers the aqueous phase is extractedthoroughly with chloroform. The combined xylene and chloroform extractsare dried over sodium sulfate and the solvents and the cyclohexanoneremoved in high vacuum. The remaining residue is taken up in hexane andchilled, upon which crystallization occurs. Yield: about 1.69 g. Theanalytically pure material obtained after recrystallization fromacetone, exhibits the following properties: IVLP. about 175-177; [M ,+6l(c., 1.1 in chlf.);

Analysis.-Calcd for C H O (370.51): C, 77.80; H, 9.25. Found: C, 77.76;H, 9.38.

C. PREPARATION OF 16fl-VIETHYL 16a,17a.-DIHYDROXY- PROGES'IERONE ZOETHYLENE KETAL To a solution of 555 mg. of A -16-methylpregnadiene-3,20-dione ZO-ethylene ketal in 45 ml. of benzene and 2.25 ml. ofpyridine is added 438 mg. of osmium tetroxide. The vessel containing thereaction mixture is stored in total darkness at room temperature for 21hours. 90 ml. of dioxane is then added and the resulting solutionsaturated with hydrogen sulfide for 7 minutes. The osmium precipitate iscentrifuged off and the clear solution added to chloroform and water.The organic layer is washed several times with water, dried over sodiumsulfate and evaporated to dryness in vacuo. There remains a crystallineresidue which after recrystallization from acetone-hexane furnishes pure16-methyl-16a,17a-dihydroxyprogesterone -ethylene ketal of the followingproperties: M.P. about 186187 and about 172174 (polymorphicmodifications); [M +74 (0., 1.38 in ehlf.); +54 (c., 1.24 in methanol);

A313, 240 mu (E:16,160); $5192.99, 6.03 and 6.23 1

Analysis.-Calcd for C H O (404.53) C, 71.25; H, 8.97. Found: C, 70.88;H, 9.19.

D. PREPARATION OF 1G 3METHYL-16a,17a.-DIHYDROXY- PROGESTERONE 16a,17a.CARBONATE ZO-ETHYLENE KETAL To a solution of 200 mg. of16B-methyl-l6a,17a-dihydroxyprogesterone 20-ethylene ketal in 6 ml. ofanhydrous pyridine is added at 0 with stirring 3 ml. of a 10% solutionof phosgene in toluene. The reaction is allowed to proceed at thattemperature for 20 minutes. Ice water is then added and the mixturetaken up in chloroform. The chloroform extract is Washed with water, 1 Nsulfuric acid, water, dilute sodium bicarbonate and again with water,dried over sodium sulfate and the solvent removed in vacuo. Theresulting residue after recrystallization from acetone-hexane furnishespure 16fl-methyl-l6a,17adihydroxyprogesterone 16a,17u-carbonateZO-ethyleneketal.

E. PREPARATION OF 16fl-METHYL16a,l7a.-DIHYDROXY PROGESTERONE16a,l7a-CARBONATE To a solution of mg. of16,8-l'l'l6lhYL160Q17a-dlhydroxyprogesterone 16a,l7a-carbonate20-ethylene ketal in 12 ml. of methanol is added 1.04 ml. of 70%perchloric acid and the mixture is stirred at room temperature for 16hours. Water is added and the solution is neutralized with sodiumbicarbonate. The bulk of the methanol is removed in vacuo and theresulting suspension extracted with chloroform. The chloroform extractis Washed with water, dried over sodium sulfate and evaporated todryness in vacuo. The residue after recrystallization from methanolyields 16l3-methyl-l6a,17a-dil1ydroxyprogesterone 16a,17m-carbonate.

F. ALTERNATIVE PREPARATION OF 1618 METHYL- l6a,17a-DIHYDROXYPROGESTERONEl6a,17a-CARBON- ATE A solution of 78 mg. ofl6fi-methyl-16a,l7a-dihydroxyprogesterone 20'ethylene ketal in 23 ml. ofmethanol and .78 ml. of 8% sulfuric acid is heated under reflux for 45minutes. The mixture is cooled, neutralized with dilute sodiumbicarbonate and after removal of the bulk of the methanol in vacuoextracted with chloroform. The chloroform extract is washed with water,dried over sodium sulfate and evaporated to dryness in vacuo. Theresidual material after recrystallization from acetone-hexane furnishespure l6B-methyl-16a,17a-dihydroxyprogesterone of the followingproperties: Ml. about 258261; [M +44 (c., .39 in chlf.);

A3 3,, 239 mu (e=17,200); kggif 2.95, 6.05 and 621 AnaZysis.Calcd for CI-1 0 (360.48): C, 73.30; H, 8.95. Found: C, 73.32; H, 8.92.

Reaction of the l6B-methyl-16a,l7a-dihydroxyprogesterone with 10%phosgene in toluene at 0 as described in part D furnishes the16,17-carbonate identical with the product obtained in part B.

EXAMPLE 5 2] -Flu0r0-1 6 04,1 7a-D ihydroxy progesterone a,]Zia-Carbonate 16a,170:,2l-trihydroxyprogesterone is treated with acetoneand perchloric acid to form 16a,17a.,21-trihydroxyprogesterone16,l7-acetonide which is then treated with mesyl chloride underanhydrous conditions at a tempera ture of 0. After two hours, water isadded and the precipitated 2l-mesylate is removed by filtration, washedthoroughly, dried in vacuo and recrystallized from acetone-hexane. Thecrystalline mesylate is dissolved in ethylene glycol and treated withpotassium bifluoride at reflux temperature for forty hours after whichthe reaction mixture is diluted with water and the crystals filteredoft", dried in vacuo and then recrystalized from acetone-hexane to yieldthe product Zl-fluOrO-l6a,l7adi hydroxyprogesterone 16a,17a-acetonide.

The 16,17-acetonide is deacetonated by treatment with 60% formic acid at100 to yield 21-fluoro-16a,l7a-dihydroxyprogesterone which is convertedby treatment with phosgene and pyridine to the product21-flt1OIO-l6a,l7ccdihydroxyprogesterone 16a,17a-carbonate.

Similarly, except for the introduction of the carbonyl group into thecorresponding 2l-chloro, 2l-bromo and 21- 7 iodo derivatives (preparedby treating the 21-mesylate with lithium chloride, lithium bromide andsodium iodide respectively) there are obtained21-chloro-16a,17a-dihydroxyprogesterone 16a,17tx-carbonate,21-bromo-16u,17adihydroxyprogesterone 16a,l7a-carbonate, and 2l-iodo-161x,l7a-dihydroxyprogesterones 16a,l7 x-carbonate, respectively.

EXAMPLE 6 60t-FlLlOI'0-160t,1 7oc-D ihydroxy progesterone 1 6 (1,17a-Carb0nate To a solution of 100 mg. of6a-fluoro-l6a,17u-dihydroxyprogesterone in 3 ml. of anhydrous pyridineis added at with stirring 1.25 ml. of a solution containing phosgene intoluene. The reaction is allowed to proceed for minutes after which timethe water is added and the mixture taken up in chloroform and Water. Thechloroform layer is separated, washed with Water, 1 N sulfuric acid,water, dilute sodium bicarbonate solution and again with Water, driedover sodium sulfate and evaporated to dryness in vacuo. The residue(about 110 mg.) after recrystallization from 95% alcohol furnishes about100 mg. of 6a-fiuoro-16a,17or-dihydroxyprogesterone 16,17-carbonatehaving the following properties: M.P. about 301-302"; [041 +122 (c.,1.04 in chlf.);

A312; 234 mu (e=l5,100); Ai? 5.53, 5.78, 5.90 and 6.14;;

AnaIysis.-Calcd for C22H27O5F (390.43): C, 67.69; H, 6.97. Found: C,67.51; H, 7.00.

EXAMPLE 7 6 zx-Ch loroJ 6 0a,] 7a-D ilzydroxy progesterone 160a,]7ot-Carb0nate Following the procedure of Example 7 an equivalent amountof 6a-chloro-l6a,17ot-dihydroxyprogesterone (prepared by treating16a,17wepoxyprogesterone in dioxane with ethyl orthoformate in ethanoland sulfuric acid to form 3 ethoxy 16oc,17zx epoxy-A -pregnadiene-20-onewhich is treated in solution with dioxane, with N-chlorosuccinimide anda sodium acetate-acetic acid buffer followed by dilution with water. Theresulting 6f3-chloro- 16a,l7a-epoxyprogester0ne dissolved in aceticacid, is treated with 33% HBr to yield 6a-chlor0-l6B-bromo-M-pregnene-17oc-ol-3,20-dione. The latter is converted to its 17tx-acetoxyderivative by treatment with acetic anhydride in 70% perchloric acid andthis product is treated with sodium acetate in acetic acid to yield6oa-Chl010- 16a,17u-dihydroxyprogesterone l6oc-3C6113t8, which isfinally treated with methanolic potassium carbonate to yield the desired6u-chloro-16a,17a-dihydroxyprogesterone) is treated with phosgene toyield the product cch1oro-16a,l7a-dihydroxyprogesterone, 16a,17acarbonate.

EXAMPLE 8 6ot-fluoro-1604,17u-dihydroxyprogesterone 16,17-carhonate ismicrobiologically 1,2-dehydrogenated in accordance with the procedure ofExample 1 of U.S. Patent No. 2,822,318 to yield the product6a-fluoro-16a,17a-dihydroxy-l-dehydroprogesterone 16a,17u-carbonate.

EXAMPLE 9 6 ,B-Fluoro-J 6 0a,] 7ot-Dihydroxyprogesterone 160a,]7u-Carb0nate A. PREPARATION OF GH-FLUOROPREGNANE-Eia,16a.,17a-TRIOL-3,20-DIONE 16a,17a-CARBONATE To a solution of 100 mg. of6fi-fluoropregnane-5a,16a, 170c-t1i0l3,20-di0116 (prepared as describedin Serial No. 859,840, filed December 16, 1959) in 3 ml. of dry pyridineis added at 0 with stirring 1.25 ml. of a solution containing 10%phosgene in toluene. The reaction is allowed to proceed for 20 minutesafter which time Water is added and the mixture taken up with chloroformand 0 Water. The chloroform layer is separated, Washed with Water, 1 Nsulfuric acid, water, dilute sodium bicarbonate solution and again withWater, dried over sodium sulfate and evaporated to dryness in vacuo. Theresidue after recrystallization from alcohol furnishes the product 6 6'-fiuoro-pregnane-5a,l6u,17a-triol-3,20-dione 1 60:,170L-C21I- bonate.

B. PREPARATION OF GH-FLUOR'O-l6a.,l7a-DIHYDROXY- PROGESTERONE16a,17a-CARBONATE To a solution of 150 mg. of 6fi-fiuoropregnane-5a,l6a,l7a-triol-3,20-dione 16u,l7a-carbonate in 6 ml. of dry pyridine is addedat 0 0.6 ml. of thionyl chloride. The mixture is allowed to stand at 0for 30 minutes, after which time ice is added and the mixture extractedwith chloroform. The chlorofrm extract is washed with 2 N hydrochloricacid, water, dilute sodium bicarbonate and again with water, dried oversodium sulfate and evaporated to dryness in vacuo. The resulting residueis dissolved in a mixture of 5 ml. of chloroform and 25 ml. of benzeneand poured through a column of l g. of neutral alumina. The ei'fiuentfurnishes crystalline material which after recrystallization fromacetone-hexane represents pure 6fl-fluoro-16a,17a-dihydroxyprogesterone16a, Not-carbonate.

The product of Example 9 can be dehydrogenated by refluxing it withchloranil in the presence of glacial acetic acid to yield 6-fiu01O-l6oc,l7a-dihydroxy-6-dehydroprogesterone 16a,17vt-carbonate.

EXAMPLE 10 6-Dehydi0-1 6 0a,] 7 a-D ihydroxy progesterone16a,17a-Carbon.ate

A solution of 250 mg. of 16a,17or-dihydroxyprogesterone16a,17a-carbonate and 500 mg. of recrystallized chloranil is heatedunder reflux in a mixture of 10 ml. of ethyl acetate and 2 ml. ofglacial acetic acid for 20 hours. The mixture is cooled, poured intowater and the layers separated. After additional extraction of theaqueous layer with ethyl acetate, the ethyl acetate extract is washedwith 1 N sodium hydroxide solution until the aqueous layer becamecolorless (7 times). (The ethyl acetate extract is washed with water,dried over sodium sulfate and evaporated to dryness in vacuo. The cruderesidue, which amounts to about 200 mg. is dissolved in benzene andchromatographed on 6 g. of neutral alumina. Elution of the column with200 ml. of benzene containing 5% chloroform, furnishes about mg. of thecrystalline carbonate ester which is analytically pure afterrecrystallization from acetone-hexane.

EXAMPLE 11 A -Pregnatriene-16a,] 7oc-Di0l-3,2 O-Dione 160a,]7oc-Carbonate The product of Example 10 is microbiologicallydehydrogenated with Bacterium cyclooxydans in accordance with theprocedure of Example 1 of US. Patent No, 2,822,318 to yield the productA -pregnatriene-16a,17adiol-3,20-dione l6zx,17a-carbonate.

EXAMPLE 12 160a,] 70,21 -Trzhydroxy-6-D ehydroprogesterone 1 6 04,17a-Carb0nate 21-Acetate The product of Example 3,l6rx,l7a,2l-trihydroxyprogesterone 160:,17oc-C31'b01121t6 Zl-acetate, istreated with chloranil in ethyl acetate and acetic acid in accordancewith the procedure of Example 10 thereby yielding the product16a,17ot,21 trihydroxy 6-dehydroprogesterone, 16oz,l7u-carbonate21-acetate.

EXAMPLE 13 6-Methyl-6-Dehydro-1 6 oc,1 7oc-D ihydroxy progesterone 16a,] 7a-Carb0nate A solution of mg. of6a-methyl-16a,17a-dihydroxyprogesterone 16o,17a-carbonate (prepared inExample 16) and 300 mg. of chloranil in a mixture of 7.5 ml. of ethylacetate and 1.5 ml. of acetic acid is heated under reflux for 42 hours.The reaction mixture is worked up as described in Example 10.Evaporation of the ethyl acetate extract in vacuo yields a residue whichis dissolved in 5 ml. of benzene and chromatographed on 4.5 g. ofneutral alumina. Elution with benzene (125 ml.) furnishes thecrystalline product, 6-methyl-6-dehydro-16u, 17a-dihydroxyprogesterone16a,17a-carbonate.

EXAMPLE 14 6 B-M ethyl-1 6 a,] 7a-D ihydroxy progesteroneI6a,17a-Carb0nrzte To a solution of 190 mg. of6fi-methylpregnane-5a,16u, 17a-trio1-3,20-dione (prepared as describedin my copending application Serial No. 764,495, filed October 1, 1958)in 5 ml. of dry pyridine is added at with stirring 2.5 ml. of a solutioncontaining 10% phosgene in toluene. The reaction is allowed to proceedfor 20 minutes and then worked up as in Example 1 to give6,8-methyl-16ot, 17a-dihydroxyprogesterone 16a,17a-carbonate.

EXAMPLE l5 6 ,8-M ethy H 6 04,1 7a-Dihydr0xy-1 -Dehydr0pr0gesterone 1 604,1 7ot-Carb0nate Treatment of the product of Example 14 in accordancewith the microbiological dehydrogenation procedure outlined in Example 1of US. Patent 2,822,318, furnishes the product6fi-methyl-16a,17u-dihydroxy-1-dehydroprogesterone 16a,l7ot-carbonate.

EXAMPLE 16 6 a-M e thy l -1 6 0a,] 7 oc-D ihy droxy progesterone 1611,]7a-Carb0nate A. PREPARATION OF 6a-METHYL16a,17a.-DIHYDROXY-PROGESTERONE' To a solution of 3.69 g. of6u-methyl-l6-dehydroprogesterone dissolved in 30 ml. of benzene and 3.6ml. of dry pyridine is added, in the dark, dropwise, With stirring overa period of 2 hours, a solution of 3 g. of osmium tetroxide in 45 ml. ofbenzene. The resulting mixture is stirred in the dark for an additional3% hours, after which 75 mil. of benzene, 138 ml. of methanol, 204 ml.of water, 21.3 g. of sodium sulfite, and 21.3 g. of potassiumbicarbonate is added and the mixture shaken for 18 hours. 250 ml. ofchloroform is then added and the resulting suspension shaken for anadditional /2 hour, filtered and the precipitate washed 3 times with 100ml. portions of hot chloroform. .After separation of the layers, theorganic layer is washed 3 times with water, dried over sodium sulfateand the solvents removed in vacuo. The resulting residue (about 4 g.) oncrystallization from acetone affords about 3.72 g. of6a-methyl-16a,17a-dihydroxyprogesterone, M.P. about 220226 C. Afterrecrystallization from acetone the pure glycol is obtained with thefollowing properties: M.P. about 224-226 0.; [a1 +68 (c., .99 in chlf.);

2.95, 5.90, 6.02, 6.25 use. 240. mu

B. PREPARATION OF 6a-METHYL-16a,17u.-DIHYDROXY- PROGESTERONE16a,17a-CARBONATE Ga-methyl-16a,17a-dihydroxyprogesterone mg.) isreacted with a solution of 1.25 ml. of phosgene in toluene in 3 n11. ofanhydrous pyridine as described in Example 6. The residue remainingafter evaporation of the chloroform in vacuo (about 113 mg.) afterrecrystallization from acetone furnishes about 92 mg. of6oc-methy1-l6oc, l7a-dihydroxyprogesterone 16a,17acarbonate having thefollowing properties: M.P. about 236-237; +122 (0., 1.04 in chlf.);

A315,; 238 mu (e=15,800); \i? 5.53, 5.79, 5.97 and 6.19 1

Analysis.-Calcd for C l-1 0 68647): C, 71.48; H, 7.82. Found: C, 71.77;H, 7.80.

EXAMPLE 17 1 6 04,1 7 cc-Z] -Trihydroxy progesterone 1 6 0a,]7a-Carb0nate The product of Example 1 is treated with an aqueoussolution of potassium carbonate at room temperature. Separation of theprecipitate from the reaction mixture yields the product 1604,17a-21trihydroxyprogesterone 16cc- Net-carbonate.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound represented by the following general formula wherein the1,2 and 6,7 positions are connected by a linkage selected from the groupconsisting of a single and a double bond; Q is a member selected fromthe group consisting of hydrogen and methyl; R is a member selected fromthe group consisting of hydrogen, lower alkyl, fluorine and chlorine;and Z is a member selected from the group consisting of hydrogen,halogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylicacid of less than ten carbon atoms.

2. 16a,l7u-dihydroxyprogesterone 16a,.17a-carbonate.

3. 21-fluoro-16u,17a-dihydroxyprogesterone 16a,17ozcarbonate.

4. 6a-fluoro-16a,17u-dihydr0xyprogesterone 1611,17 ozcarbonate.

5. 6a-methyl-16a,17a-dihydroxyprogesterone 16u,17ucarbonate.

References Cited in the file of this patent Noller: Chemistry of OrganicCompounds, W. B. Saunders Co., Philadelphia, Pa. (1957), p. 741,

1. A COMPOUND REPRESENTED BY THE FOLLOWING GENERAL FORMULA